We developed two imaging technologies, cryo fluorescence tomography and cryo soft x-ray tomography, to examine the position of molecules with respect to cell structures. We first use fluorescence tomography to reveal the 3-D location of proteins, then soft x-ray tomography of the same cell to place those proteins into the structural organization of the cell. The two complementary tomographic reconstructions are co-aligned and overlaid to produce 3-D views of the protein on cell structures. Cryo-immobilization is used to assure all proteins remain in the same position while collecting images from multiple angles around the cell, and tomography yields isotropic resolution. With soft x-ray tomography, images are collecting using photons in the ‘water window’ (between the K shell edges of carbon and nitrogen), where biomolecules absorb an order of magnitude more than water. Since absorption adheres to the Beer-Lambert Law and is linear with chemical composition and concentration of organic material, cell structures have unique Linear Absorption Coefficient (LAC) measurements. Consequently structures such as lipid drops are more absorbing, and have higher contrast, than fluid-filled vacuoles that are less absorbing. We used these technologies to show that differentiation of mouse olfactory epithelial cells and hematopoietic cells coincides with a gradual increase in chromatin compaction, and that this process is regulated by the heterochromatin binding protein HP1beta and H3K9 methylation. In a separate study, we used MacroH2A-GFP to locate the inactive X chromosome (Xi) in nuclei of intact cells. Using soft x-ray tomography LAC values, we were able to identify three distinct structural regions in the Xi that have different degrees of ‘crowding’ or ‘compaction’. Finally, we demonstrate that correlated fluorescence and x-ray tomography can be used as an in vivo FISH approach to precisely position transcription factors in the context of nuclear structures.